Chloe Sligar, Ellie Reilly, Peter Cuthbertson, Kara L Vine, Katrina M Bird, Amal Elhage, Stephen I Alexander, Ronald Sluyter, Debbie Watson
{"title":"在人源化小鼠移植后单独使用环磷酰胺或与托珠单抗联合使用后,移植物抗白血病免疫力得以保留","authors":"Chloe Sligar, Ellie Reilly, Peter Cuthbertson, Kara L Vine, Katrina M Bird, Amal Elhage, Stephen I Alexander, Ronald Sluyter, Debbie Watson","doi":"10.1002/cti2.1497","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objectives</h3>\n \n <p>Donor haematopoietic stem cell transplantation treats leukaemia by inducing graft-versus-leukaemia (GVL) immunity. However, this benefit is often mitigated by graft-versus-host disease (GVHD), which is reduced by post-transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>NOD-<i>scid</i>-IL2Rγ<sup>null</sup> mice were injected with 2 × 10<sup>7</sup> human peripheral blood mononuclear cells (hPBMCs) on day 0 and with 1 × 10<sup>6</sup> THP-1 acute myeloid leukaemia cells on day 14. In subsequent experiments, mice were also injected with PTCy (33 mg kg<sup>−1</sup>) or Dulbecco's phosphate buffered saline (PBS) on days 3 and 4, alone or combined with TOC or control antibody (25 mg kg<sup>−1</sup>) twice weekly for 28 days. Clinical signs of disease were monitored until day 42.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Mice with hPBMCs from three different donors and THP-1 cells showed similar survival, clinical score and weight loss. hCD33<sup>+</sup> leukaemia cells were minimal in mice reconstituted with hPBMCs from two donors but present in mice with hPBMCs from a third donor, suggesting donor-specific GVL responses. hPBMC-injected mice treated with PTCy alone or combined with TOC (PTCy + TOC) demonstrated prolonged survival compared to control mice. PTCy alone and PTCy + TOC-treated mice with hPBMCs showed minimal hepatic hCD33<sup>+</sup> leukaemia cells, indicating sustained GVL immunity. Further, the combination of PTCy + TOC reduced histological damage in the lung and liver.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>Collectively, this research demonstrates that PTCy alone or combined with TOC impairs GVHD without compromising GVL immunity.</p>\n </section>\n </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 3","pages":""},"PeriodicalIF":4.6000,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1497","citationCount":"0","resultStr":"{\"title\":\"Graft-versus-leukaemia immunity is retained following treatment with post-transplant cyclophosphamide alone or combined with tocilizumab in humanised mice\",\"authors\":\"Chloe Sligar, Ellie Reilly, Peter Cuthbertson, Kara L Vine, Katrina M Bird, Amal Elhage, Stephen I Alexander, Ronald Sluyter, Debbie Watson\",\"doi\":\"10.1002/cti2.1497\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Objectives</h3>\\n \\n <p>Donor haematopoietic stem cell transplantation treats leukaemia by inducing graft-versus-leukaemia (GVL) immunity. However, this benefit is often mitigated by graft-versus-host disease (GVHD), which is reduced by post-transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>NOD-<i>scid</i>-IL2Rγ<sup>null</sup> mice were injected with 2 × 10<sup>7</sup> human peripheral blood mononuclear cells (hPBMCs) on day 0 and with 1 × 10<sup>6</sup> THP-1 acute myeloid leukaemia cells on day 14. In subsequent experiments, mice were also injected with PTCy (33 mg kg<sup>−1</sup>) or Dulbecco's phosphate buffered saline (PBS) on days 3 and 4, alone or combined with TOC or control antibody (25 mg kg<sup>−1</sup>) twice weekly for 28 days. Clinical signs of disease were monitored until day 42.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Mice with hPBMCs from three different donors and THP-1 cells showed similar survival, clinical score and weight loss. hCD33<sup>+</sup> leukaemia cells were minimal in mice reconstituted with hPBMCs from two donors but present in mice with hPBMCs from a third donor, suggesting donor-specific GVL responses. hPBMC-injected mice treated with PTCy alone or combined with TOC (PTCy + TOC) demonstrated prolonged survival compared to control mice. PTCy alone and PTCy + TOC-treated mice with hPBMCs showed minimal hepatic hCD33<sup>+</sup> leukaemia cells, indicating sustained GVL immunity. 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Graft-versus-leukaemia immunity is retained following treatment with post-transplant cyclophosphamide alone or combined with tocilizumab in humanised mice
Objectives
Donor haematopoietic stem cell transplantation treats leukaemia by inducing graft-versus-leukaemia (GVL) immunity. However, this benefit is often mitigated by graft-versus-host disease (GVHD), which is reduced by post-transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity.
Methods
NOD-scid-IL2Rγnull mice were injected with 2 × 107 human peripheral blood mononuclear cells (hPBMCs) on day 0 and with 1 × 106 THP-1 acute myeloid leukaemia cells on day 14. In subsequent experiments, mice were also injected with PTCy (33 mg kg−1) or Dulbecco's phosphate buffered saline (PBS) on days 3 and 4, alone or combined with TOC or control antibody (25 mg kg−1) twice weekly for 28 days. Clinical signs of disease were monitored until day 42.
Results
Mice with hPBMCs from three different donors and THP-1 cells showed similar survival, clinical score and weight loss. hCD33+ leukaemia cells were minimal in mice reconstituted with hPBMCs from two donors but present in mice with hPBMCs from a third donor, suggesting donor-specific GVL responses. hPBMC-injected mice treated with PTCy alone or combined with TOC (PTCy + TOC) demonstrated prolonged survival compared to control mice. PTCy alone and PTCy + TOC-treated mice with hPBMCs showed minimal hepatic hCD33+ leukaemia cells, indicating sustained GVL immunity. Further, the combination of PTCy + TOC reduced histological damage in the lung and liver.
Conclusion
Collectively, this research demonstrates that PTCy alone or combined with TOC impairs GVHD without compromising GVL immunity.
期刊介绍:
Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.